A nuclear receptor is a ligand-activated transcription factor. FXR is a very important member of nuclear receptors in humans, which plays an important regulating role in serious diseases of metabolism, inflammation, tumor, etc. and in the relevant physiological function. The FXR ligand mediated pharmacological action principle is that a ligand binds to the ligand binding domain (LBD) of FXR, thereby recruiting various coactivators (or corepressors) to regulate downstream target genes. In the body, bile acid is an endogenous ligand of FXR, the activation of FXR can maintain normal circulation and homeostasis of bile acid in the liver and small intestine, and can meanwhile regulate the levels of saccharides, lipids and cholesterol. FXR is involved in many signal pathways associated with metabolism, and has become a remarkable target molecule of a medicament for treating metabolic diseases such as hyperglycemia, insulin resistance, hypertriglyceridemia, hypercholesterolemia, diabetes, obesity, cholestasia, gallstones, non-alcoholic fatty liver, and atherosclerosis. Recently it has been found that FXR can regulate the regeneration of the liver, and the knockout of the FXR gene in a mouse can result in the development of liver cancer. Chenodeoxycholic acid (abbreviated as CDCA) is a type of bile acid which can bind to and activate FXR and can be used for treating gallstones. Among the ligands capable of binding to FXR, CDCA is the only medicament which is used clinically. However, the affinity of CDCA to FXR is far lower than that of synthetic ligand GW4064 of FXR, furthermore CDCA can also bind to bile acid binding protein (I-BABP), bile acid transporter and other proteins; therefore, CDCA is also not a medicament specifically targeting FXR. About 13% of the existing medicaments target nuclear receptors, and based on the important physiological action regulated by FXR, screening new ligand medicaments targeting FXR and optimizing, designing and developing the ligand medicaments have an important application value.
Ivermectin and doramectin are derivatives of macrolide abamectin/avermectin produced by streptomycetes, and have a highly effective and broad-spectrum antiparasitic effect, wherein ivermectin, doramectin and abamectin/avermectin are mainly used in controlling livestock parasites and treating filarial infection in humans. There are reports which had suggested that the targets of ivermectin in invertebrates are receptors such as γ-aminobutyric acid (GABA) receptor and glutamic acid mediated chloride ion channel receptor (GluClR). There is no report that there is a target of abamectin/avermectin and its derivatives with high-affinity and specificity in a mammal as of yet.